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Sex and steroid hormones in early brain injury

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Abstract

Brain injury during development can have severe, long-term consequences. Using an array of animal models, we have an understanding of the etiology of perinatal brain injury. However, we have only recently begun to address the consequences of endogenous factors such as genetic sex and developmental steroid hormone milieu. Our limited understanding has sometimes led researchers to make over-generalizing and potentially dangerous statements regarding treatment for brain injury. Therefore this review acts as a cautionary tale, speaking to our need to understand the effects of sex and steroid hormone environment on the response to brain trauma in the neonate.

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References

  1. Nikonenko AG, Radenovic L, Andjus PR, Skibo CG. Structural features of ischemic damage in the hippocampus. Anat Rec. 2009;292:1914–21.

    Article  CAS  Google Scholar 

  2. Vannucci RC, Vannucci SJ. Perinatal hypoxic-ischemic brain damage: Evolution of an animal model. Dev Neurosci. 2005;27:81–6.

    Article  PubMed  CAS  Google Scholar 

  3. Andine P, Thordstein M, Kjellmer I, Nordborg C, Thiringer K, Wennberg E, Hagberg H. Evaluation of brain damage in a rat model of neonatal hypoxic-ischemia. J Neurosci Methods. 1990;35:253–60.

    Article  PubMed  CAS  Google Scholar 

  4. Nyakas C, Buwalda B, Luiten PG. Hypoxia and brain development. Prog Neurobiol. 1996;49:1–51.

    PubMed  CAS  Google Scholar 

  5. Vannucci RC. Experimental biology of cerebral hypoxia-ischemia: Relation to perinatal brain damage. Pediatr Res. 1990;27:317–26.

    Article  PubMed  CAS  Google Scholar 

  6. Simon NP. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol. 1999;26:767–78.

    PubMed  CAS  Google Scholar 

  7. Durham JL, Jordan KA, Devos MJ, Williams EK, Sandstrom NJ. Estradiol protects against hippocampal damage and impairment in fear conditioning resulting from transient global ischemia in mice. Brain Res.; 2012. In press.

  8. Ulbrich C, Zendedel A, Habib P, Kipp M, Beyer C, Dang J. Long term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia. J Steroid Biochem Mol Biol.; 2012. In press.

  9. Wang LC, Huang CY, Wang HK, Wu MH, Tsai KJ. Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after transient focal ischemia. J Neurotrauma.; 2012.

  10. Yang Q, Fang W, Lv P, Geng X, Sha L. Therapeutic neuroprotective effects of XQ-11 in a rat model of permanent focal cerebral ischemia. Pharmacology. 2011;89:1–6.

    Article  PubMed  CAS  Google Scholar 

  11. Levine S. Anoxic-ischemic encephalopathy in rats. Am J Pathol. 1960;36:1–17.

    PubMed  CAS  Google Scholar 

  12. Bernal F, Saura J, Ojuel J, Mahy N. Differential vulnerability of hippocampus, basal ganglia, and prefrontal cortex to long-term NMDA excitotoxicity. Exp Neurol. 2000;161:686–95.

    Article  PubMed  CAS  Google Scholar 

  13. Rice JE, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981;9:131–41.

    Article  PubMed  Google Scholar 

  14. Vannucci RC. Experimental models of perinatal hypoxic-ischemic brain damage. APMIS Suppl. 1993;40:89–95.

    PubMed  CAS  Google Scholar 

  15. Turtzo LC, McCullough LD. Sex-specific responses to stroke. Future Neurol. 2010;5:47–59.

    Article  PubMed  Google Scholar 

  16. Perlman JM. Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther. 2006;28:1353–65.

    Article  PubMed  CAS  Google Scholar 

  17. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol. 2004;207:3149–54.

    Article  PubMed  CAS  Google Scholar 

  18. Vannucci RC. Hypoxic-ischemic encephalopathy. Am J Perinatol. 2000;17:113–20.

    Article  PubMed  CAS  Google Scholar 

  19. Volpe JJ. Brain injury in the premature infant–current concepts of pathogenesis and prevention. Biol Neonate. 1992;62:231–42.

    Article  PubMed  CAS  Google Scholar 

  20. Thompson DK, Wood SJ, Doyle LW, Warfield SK, Lodygensky GA, Anderson PJ, Egan GF, Inder TE. Neonate hippocampal volumes: Prematurity, perinatal predictors, and 2-year outcome. Ann Neurol. 2008;63:642–51.

    Article  PubMed  Google Scholar 

  21. Broadbent NJ, Squire LR, Clark RE. Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci USA. 2004;101:14515–20.

    Article  PubMed  CAS  Google Scholar 

  22. Ergorul C, Eichenbaum H. The hippocampus and memory for “what,” “where,” and “when”. Learn Mem. 2004;11:397–405.

    Article  PubMed  Google Scholar 

  23. Jarrard LE. What does the hippocampus really do? Behav Brain Res. 1995;71:1–10.

    Article  PubMed  CAS  Google Scholar 

  24. Nadel L, Hardt O. The spatial brain. Neuropsychology. 2004;18:473–6.

    Article  PubMed  Google Scholar 

  25. Feldman S, Conforti N, Weidenfeld J. Limbic pathways and hypothalamic neurotransmitters mediating adrenocortical responses to neural stimuli. Neurosci Biobehav Rev. 1995;19:235–40.

    Article  PubMed  CAS  Google Scholar 

  26. Sapolsky RM, Meaney MJ, McEwen BS. The development of the glucocorticoid receptor system in the rat limbic brain. III Negative-feedback regulation Brain Res. 1985;350:169–73.

    CAS  Google Scholar 

  27. Simon RP, Griffiths T, Evans MC, Swan JH, Meldrum BS. Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: An electron microscopy study in the rat. J Cereb Blood Flow Metab. 1984;4:350–61.

    Article  PubMed  CAS  Google Scholar 

  28. Redecker R, Adami A, Tone B, Tian HR, Lalas S, Hartman RE, Obenaus A, Ashwal S. Rodent neonatal bilateral carotid artery occlusion with hypoxia mimics human hypoxic-ischemic injury. J Cereb Blood Flow Metab. 2009;29:1305–16.

    Article  Google Scholar 

  29. Yang T, Zhuang L, Terrando N, Wu X, Jonhson MR, Maze M, Ma D. A clinically relevant model of perinatal global ischemic brain damage in rats. Brain Res. 2011;1383:317–23.

    Article  PubMed  CAS  Google Scholar 

  30. Kaindl AM, Favrais G, Gressens P. Molecular mechanisms involved in injury to the preterm brain. J Child Neurol. 2009;24:1112–8.

    Article  PubMed  Google Scholar 

  31. Rees S, Harding R, Walker D. The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int J Dev Neurosci. 2011;29:551–63.

    Article  PubMed  Google Scholar 

  32. Lee AL, Ogle WO, Sapolsky RM. Stress and depression: Possible links to neuron death in the hippocampus. Bipolar Disord. 2002;4:117–28.

    Article  PubMed  CAS  Google Scholar 

  33. Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamäki H, Karjalainen AK, Lehtonen J. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med. 2000;30:117–25.

    Article  PubMed  CAS  Google Scholar 

  34. Sapolsky RM. Depression, antidepressants, and the shrinking hippocampus. Proc Natl Acad Sci USA. 2001;98:12320–2.

    Article  PubMed  CAS  Google Scholar 

  35. Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: A primer on neuron death. Biol Psychiatry. 2000;48:755–65.

    Article  PubMed  CAS  Google Scholar 

  36. O’Regan D, Welberg LL, Holmes MC, Seckl JR. Glucocorticoid programming of pituitary-adrenal function: Mechanisms and physiological consequences. Semin Neonatol. 2001;6:319–29.

    Article  PubMed  Google Scholar 

  37. Vázquez DM. Stress and the developing limbic-hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology. 1998;23:663–700.

    Article  PubMed  Google Scholar 

  38. Herman JP, Cullinan WE. Neurocircuitry of stress: Central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 1997;20:78–84.

    Article  PubMed  CAS  Google Scholar 

  39. Gothelf D, Soreni N, Nachman RP, Tyano S, Hiss Y, Reiner O, Weizman A. Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. Eur Neuropsychopharmacol. 2000;10:389–95.

    Article  PubMed  CAS  Google Scholar 

  40. Lawrie SM, Whalley HC, Abukmeil SS, Kestelman JN, Miller P, Best JJ, Owens DG, Johnstone EC. Temporal lobe volume changes in people at high risk of schizophrenia with psychotic symptoms. Br J Psychiatry. 2002;181:138–43.

    PubMed  Google Scholar 

  41. Seidman LJ, Faraone SV, Goldstein JM, Kremen WS, Horton NJ, Makris N, Toomey R, Kennedy D, Caviness VS, Tsuang MT. Left hippocampal volume as a vulnerability indicator for schizophrenia: A magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry. 2002;59:839–49.

    Article  PubMed  Google Scholar 

  42. Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP. Developmental neurobiology of childhood stress and trauma. Psychiatr Clin North Am. 2002;25:397–426.

    Article  PubMed  Google Scholar 

  43. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997;27:951–9.

    Article  PubMed  CAS  Google Scholar 

  44. Bremner JD. Alterations in brain structure and function associated with post-traumatic stress disorder. Semin Clin Neuropsychiatry. 1999;4:249–55.

    PubMed  CAS  Google Scholar 

  45. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, Brummer M, Staib L, Vermetten E, Charney DS, Nemeroff CB, Bremner JD. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072–80.

    Article  PubMed  Google Scholar 

  46. Bremner JD. Hypotheses and controversies related to effects of stress on the hippocampus: An argument for stress-induced damage to the hippocampus in patients with posttraumatic stress disorder. Hippocampus. 2001;11:75–81.

    Article  PubMed  CAS  Google Scholar 

  47. McEwen BS, Woolley CS. Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol. 1994;29:431–6.

    Article  PubMed  CAS  Google Scholar 

  48. Marrif H, Juurlink BH. Astrocytes respond to hypoxia by increasing glycolytic capacity. J Neurosci Res. 1999;57:255–60.

    Article  PubMed  CAS  Google Scholar 

  49. Goldstein P, Kroemer G. Cell death by necrosis: Towards a molecular definition. Trends Biochem Sci. 2007;32:37–43.

    Article  CAS  Google Scholar 

  50. Cataltepe O, Towfighi J, Vannucci RC. Cerebrospinal fluid concentrations of glutamate and GABA during perinatal cerebral hypoxia-ischemia and seizures. Brain Res. 1996;709:326–30.

    Article  PubMed  CAS  Google Scholar 

  51. Hedner T, Iversen K, Lundborg P. gamma-Aminobutyric acid concentrations in the cerebrospinal fluid of newborn infants. Early Hum Dev. 1982;7:53–8.

    Article  PubMed  CAS  Google Scholar 

  52. Iversen K, Hedner T, Lundborg P. GABA concentrations and turnover in neonatal rat brain during asphyxia and recovery. Acta Physiol Scand. 1983;118:91–4.

    Article  PubMed  CAS  Google Scholar 

  53. Saransaari P, Oja SS. Enhanced GABA release in cell-damaging conditions in the adult and developing mouse hippocampus. Int J Dev Neurosci. 1997;15:163–74.

    Article  PubMed  CAS  Google Scholar 

  54. Wallin C, Puka-Sundvall M, Hagberg H, Weber SG, Sandberg M. Alterations in glutathione and amino acid concentrations after hypoxia-ischemia in the immature rat brain. Dev Brain Res. 2000;125:51–60.

    Article  CAS  Google Scholar 

  55. Olney JW, Ho OL. Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature. 1970;227:609–11.

    Article  PubMed  CAS  Google Scholar 

  56. Johnston MV. Excitotoxicity in neonatal hypoxia. Ment Retard Dev Disabil Res Rev. 2001;7:229–34.

    Article  PubMed  CAS  Google Scholar 

  57. Marks JD, Bindokas VP, Zhang XM. Maturation of vulnerability to excitotoxicity: Intracellular mechanisms in cultured postnatal hippocampal neurons. Dev Brain Res. 2000;124:101–16.

    Article  CAS  Google Scholar 

  58. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev. 1990;15:41–70.

    Article  PubMed  Google Scholar 

  59. Vergun O, Keelan J, Khodorov BI, Duchen MR. Glutamate-induced mitochondrial depolarisation and perturbation of calcium homeostasis in cultured rat hippocampal neurones. J Physiol. 1999;519:451–66.

    Article  PubMed  CAS  Google Scholar 

  60. Volpe JJ. Perinatal brain injury: From pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev. 2001;7:56–64.

    Article  PubMed  CAS  Google Scholar 

  61. Buresh Y, Koroleva VI, Korolev OS, Maresh V. Changes in the constant potential in brain structures in rats during focal ischemia and systemic hypoxia. Neurosci Behav Physiol. 1999;29:569–79.

    Article  PubMed  CAS  Google Scholar 

  62. Ouyang C, Guo L, Lu Q, Xu X, Wang H. Enhanced activity of GABA receptors inhibits glutamate release induced by focal cerebral ischemia in rat striatum. Neurosci Lett. 2007;420:174–8.

    Article  PubMed  CAS  Google Scholar 

  63. Auger AP, Perrot-Sinal TS, McCarthy MM. Excitatory versus inhibitory GABA as a divergence point in steroid-mediated sexual differentiation of the brain. Proc Natl Acad Sci USA. 2001;98:8059–64.

    Article  PubMed  CAS  Google Scholar 

  64. McCarthy MM. Getting excited about GABA and sex differences in the brain. Trends Neurosci. 2002;25:307–12.

    Article  PubMed  CAS  Google Scholar 

  65. Perrot-Sinal TS, Auger AP, McCarthy MM. Excitatory actions of GABA in developing brain are mediated by l-type Ca2+ channels and dependent on age, sex and brain region. Neuroscience. 2003;116:995–1003.

    Article  PubMed  CAS  Google Scholar 

  66. Nuñez JL, Alt JJ, McCarthy MM. A new model for prenatal brain damage: I. GABAA receptor activation induces cell death in developing rat hippocampus. Exp Neurol. 2003;181:258–69.

    Article  PubMed  CAS  Google Scholar 

  67. Hagberg H, Ichord R, Palmer C, Yager JY, Vannucci SJ. Animal models of developmental brain injury: Relevance to human disease. A summary of the panel discussion from the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism. Dev Neurosci. 2002;24:364–6.

    Article  PubMed  CAS  Google Scholar 

  68. Green PS, Simpkins JW. Neuroprotective effects of estrogens: Potential mechanisms of action. Int J Dev Neurosci. 2000;18:347–58.

    Article  PubMed  CAS  Google Scholar 

  69. Liu M, Dziennis S, Hurn PD, Alkayed NJ. Mechanisms of gender-linked ischemic brain injury. Restor Neurol Neurosci. 2009;27:163–79.

    PubMed  CAS  Google Scholar 

  70. McCarthy MM, Konkle AT. When is a sex difference not a sex difference? Front Neuroendocrinol. 2005;26:85–102.

    Article  PubMed  CAS  Google Scholar 

  71. Singer CA, Rogers KL, Strickland TM, Dorsa DM. Estrogen protects primary cortical neurons from glutamate toxicity. Neurosci Lett. 1996;212:13–6.

    Article  PubMed  CAS  Google Scholar 

  72. Stein DG. Sex differences in brain damage and recovery of function: Experimental and clinical findings. Prog Brain Res. 2007;161:339–51.

    Article  PubMed  CAS  Google Scholar 

  73. Suzuki S, Brown CM, Wise PM. Mechanisms of neuroprotection by estrogen. Endocrine. 2006;29:209–15.

    Article  PubMed  CAS  Google Scholar 

  74. Wise PM, Dubal DB, Wilson ME, Rau SW, Böttner M, Rosewell KL. Estradiol is a protective factor in the adult and aging brain: Understanding of mechanisms derived from in vivo and in vitro studies. Brain Res Rev. 2001;37:313–9.

    Article  PubMed  CAS  Google Scholar 

  75. Yager JY, Wright S, Armstrong EA, Jahraus CM, Saucier DM. A new model for determining the influence of age and sex on functional recovery following hypoxic-ischemic brain damage. Dev Neurosci. 2005;27:112–20.

    Article  PubMed  CAS  Google Scholar 

  76. Zhao L, Brinton RD. Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+) dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons. Brain Res. 2007;1172:48–59.

    Article  PubMed  CAS  Google Scholar 

  77. Hines M. Estrogenic contributions to sexual differentiation in the female guinea pig: Influences of diethylstilbestrol and tamoxifen on neural, behavioral, and ovarian development. Horm Behav. 1987;21:402–17.

    Article  PubMed  CAS  Google Scholar 

  78. MacLusky NJ, Lieberburg I, McEwen BS. The development of estrogen receptor systems in the rat brain: Perinatal development. Brain Res. 1979;178:129–42.

    Article  PubMed  CAS  Google Scholar 

  79. McCarthy MM, Schlenker EH, Pfaff DW. Enduring consequences of neonatal treatment with antisense oligodeoxynucleotides to estrogen receptor messenger ribonucleic acid on sexual differentiation of rat brain. Endocrinology. 1993;133:433–9.

    Article  PubMed  CAS  Google Scholar 

  80. McEwen BS, Lieberburg I, MacLusky N, Plapinger L. Do estrogen receptors play a role in the sexual differentiation of the rat brain? J Steroid Biochem. 1977;8:593–8.

    Article  PubMed  CAS  Google Scholar 

  81. Naftolin F, Garcia-Segura LM, Keefe D, Leranth C, MacLusky NJ, Brawer JR. Estrogen effects on the synaptology and neural membranes of the rat hypothalamic arcuate nucleus. Biol Reprod. 1990;42:21–8.

    Article  PubMed  CAS  Google Scholar 

  82. MacLusky NJ, Clark AS, Naftolin F, Goldman-Rakic PS. Estrogen formation in the mammalian brain: Possible role of aromatase in sexual differentiation of the hippocampus and neocortex. Steroids. 1987;50:459–74.

    Article  PubMed  CAS  Google Scholar 

  83. MacLusky NJ, Walters MJ, Clark AS, Toran-Allerand CD. Aromatase in the cerebral cortex, hippocampus, and mid-brain: Ontogeny and developmental implications. Mol Cell Neurosci. 1994;5:691–8.

    Article  PubMed  CAS  Google Scholar 

  84. McEwen BS, Lieberburg I, Chaptal C, Krey LC. Aromatization: Important for sexual differentiation of the neonatal rat brain. Horm Behav. 1977;9:249–63.

    Article  PubMed  CAS  Google Scholar 

  85. Naftolin F. Brain aromatization of androgens. J Reprod Med. 1994;39:257–61.

    PubMed  CAS  Google Scholar 

  86. Benassayag C, Vallette G, Delorme J, Savu L, Nunez EA, Jayle MF. Rat and human embryo and post-natal sera contain a potent endogenous competitor of estrogen-rat alpha-fetoprotein interactions. Steroids. 1977;30:771–85.

    Article  PubMed  CAS  Google Scholar 

  87. MacLusky NJ, Chaptal C, McEwen BS. The development of estrogen receptor systems in the rat brain and pituitary: Perinatal development. Brain Res. 1979;178:129–42.

    Article  PubMed  CAS  Google Scholar 

  88. MacLusky NJ, Chaptal C, McEwen BS. The development of estrogen receptor systems in the rat brain and pituitary: Postnatal development. Brain Res. 1979;178:143–60.

    Article  PubMed  CAS  Google Scholar 

  89. Lieberburg I, Krey LC, McEwen BS. Sex differences in serum testosterone and in exchangeable brain cell nuclear estradiol during the neonatal period in rats. Brain Res. 1979;178:207–12.

    Article  PubMed  CAS  Google Scholar 

  90. Naftolin F, Ryan KJ, Petro Z. Aromatization of androstenedione by the diencephalon. J Clin Endocrinol Metab. 1971;33:368–70.

    Article  PubMed  CAS  Google Scholar 

  91. Rhoda J, Corbier P, Roffi J. Gonadal steroid concentrations in serum and hypothalamus of the rat at birth: Aromatization of testosterone to 17 beta-estradiol. Endocrinology. 1984;114:1754–60.

    Article  PubMed  CAS  Google Scholar 

  92. Corbier P. Changes in testicular weight and serum gonadotropin and testosterone levels before, during, and after birth in the perinatal rat. Endocrinology. 1978;103:1985–91.

    Article  PubMed  CAS  Google Scholar 

  93. Weisz J, Ward IL. Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology. 1980;106:306–16.

    Article  PubMed  CAS  Google Scholar 

  94. Sokka TA, Huhtaniemi IT. Functional maturation of the pituitary-gonadal axis in the neonatal female rat. Biol Reprod. 1995;52:1404–9.

    Article  PubMed  CAS  Google Scholar 

  95. Kretz O, Fester L, Wehrenberg U, Zhou L, Brauckmann S, Zhao S, Prange-Kiel J, Naumann T, Jarry H, Frotscher M, Rune GM. Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci. 2004;24:5913–21.

    Article  PubMed  CAS  Google Scholar 

  96. Prange-Kiel J, Fester L, Zhou L, Lauke H, Carrétero J, Rune GM. Inhibition of hippocampal estrogen synthesis causes region-specific downregulation of synaptic protein expression in hippocampal neurons. Hippocampus. 2006;16:464–71.

    Article  PubMed  CAS  Google Scholar 

  97. Prange-Kiel J, Rune GM. Direct and indirect effects of estrogen on rat hippocampus. Neuroscience. 2006;138:765–72.

    Article  PubMed  CAS  Google Scholar 

  98. Rune GM, Lohse C, Prange-Kiel J, Fester L, Frotscher M. Synaptic plasticity in the hippocampus: Effects of estrogen from the gonads or hippocampus? Neurochem Res. 2006;31:145–55.

    Article  PubMed  CAS  Google Scholar 

  99. Amateau SK, Alt JJ, Stamps CL, McCarthy MM. Brain estradiol content in newborn rats: Sex differences, regional heterogeneity, and possible de novo synthesis by the female telencephalon. Endocrinology. 2004;145:2906–17.

    Article  PubMed  CAS  Google Scholar 

  100. Arteni NS, Pereira LO, Rodrigues AL, Lavinsky D, Achaval ME, Netto CA. Lateralized and sex-dependent effects of unilateral neonatal cerebral hypoxia-ischemia in the rat. Behav Brain Res. 2010;210:92–8.

    Article  PubMed  CAS  Google Scholar 

  101. Hill CA, Threlkeld SW, Fitch RH. Early testosterone modulated sex differences in behavioral outcome following neonatal hypoxia ischemia in rats. Int J Dev Neurosci. 2011;29:381–8.

    Article  PubMed  CAS  Google Scholar 

  102. Hill CA, Alexander ML, McCullough LD, Fitch RH. Inhibition of x-linked inhibitor of apoptosis with embelin differentially affects male versus female behavioral outcome following neonatal hypoxia ischemia in rats. Dev Neurosci. 2011;33:494–504.

    Article  PubMed  CAS  Google Scholar 

  103. Mayoral SR, Omar G, Penn AA. Sex differences in a hypoxia model of preterm brain damage. Pediatr Res. 2009;66:248–53.

    Article  PubMed  Google Scholar 

  104. Weiss SN, Pettenuzzo LF, Krolow R, Valentim LM, Mota CS, Dalmaz C, Wyse AT, Netto CA. Neonatal hypoxia-ischemia induces sex related changes in rat brain mitochondria. Mitochondrion; 2011. In press.

  105. Nuñez J, Yang Z, Jiang Y, Grandys T, Mark I, Levison SW. 17beta estradiol protects the neonatal brain from hypoxia-ischemia. Exp Neurol. 2007;208:269–76.

    Article  PubMed  CAS  Google Scholar 

  106. Gestner B, Lee J, DeSilva TM, Jensen FE, Volpe JJ, Rosenberg PA. 17beta estradiol protects against hypoxic/ischemic white matter damage in the neonatal rat brain. J Neurosci Res. 2009;87:2078–86.

    Article  CAS  Google Scholar 

  107. Fatehi M, Kombian SB, Saleh TM. 17beta-estradiol inhibits outward potassium currents recorded in rat parabrachial nucleus cells in vitro. Neuroscience. 2005;135:1075–86.

    Article  PubMed  CAS  Google Scholar 

  108. Fatehi M, Zidichouski JA, Kombian SB, Saleh TM. 17beta-estradiol attenuates excitatory neurotransmission and enhances the excitability of rat parabrachial neurons in vitro. J Neurosci Res. 2006;84:666–74.

    Article  PubMed  Google Scholar 

  109. Rao SP, Sikdar SK. Estradiol-induced changes in the activity of hippocampal neurons in network culture are suppressed by co-incubation with gabapentin. Brain Res. 2004;1022:126–36.

    Article  PubMed  CAS  Google Scholar 

  110. Woolley CS, Weiland NG, McEwen BS, Schwartzkroin PA. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: Correlation with dendritic spine density. J Neurosci. 1997;17:1848–59.

    PubMed  CAS  Google Scholar 

  111. Boulware MI, Weick JP, Becklund BR, Kuo SP, Groth RD, Mermelstein PG. Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci. 2005;25:5066–78.

    Article  PubMed  CAS  Google Scholar 

  112. Hilton GD, Nunez JL, Bambrick L, Thompson SM, McCarthy MM. Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol. Eur J Neurosci. 2006;24:3008–16.

    Article  PubMed  Google Scholar 

  113. Smith CC, McMahon LL. Estradiol-induced increase in the magnitude of long-term potentiation is prevented by blocking NR2B-containing receptors. J Neurosci. 2006;26:8517–22.

    Article  PubMed  CAS  Google Scholar 

  114. Snyder MA, Cooke BM, Woolley CS. Estradiol potentiation of NR2B-dependent EPSCs is not due to changes in NR2B protein expression or phosphorylation. Hippocampus. 2011;21:398–408.

    Article  PubMed  CAS  Google Scholar 

  115. Khodorov B. Glutamate induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurons. Prog Biophys Mol Biol. 2004;86:279–351.

    Article  PubMed  CAS  Google Scholar 

  116. Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, Graham SH, Clark RS. Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem. 2004;279:38563–70.

    Article  PubMed  CAS  Google Scholar 

  117. Flynn JM, Cammarata PR. Estradiol attenuates mitochondrial depolarization in polyol-stressed lens epithelial cells. Mol Vis. 2006;12:271–82.

    PubMed  CAS  Google Scholar 

  118. Kramár EA, Chen LY, Brandon NJ, Rex CS, Liu F, Gall CM, Lynch G. Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity. J Neurosci. 2009;29:12982–93.

    Article  PubMed  CAS  Google Scholar 

  119. Lee DY, Chai YG, Lee EB, Kim KW, Nah SY, Oh TH, Rhim H. 17Beta-estradiol inhibits high-voltage-activated calcium channel currents in rat sensory neurons via a non-genomic mechanism. Life Sci. 2002;70:2047–59.

    Article  PubMed  CAS  Google Scholar 

  120. Wu TW, Wang JM, Chen S, Brinton RD. 17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: A potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience. 2005;135:59–72.

    Article  PubMed  CAS  Google Scholar 

  121. Zhang L, Li PP, Feng X, Barker JL, Smith SV, Rubinow DR. Sex-related differences in neuronal cell survival and signaling in rats. Neurosci Lett. 2003;337:65–8.

    Article  PubMed  CAS  Google Scholar 

  122. Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K, Hagberg H. Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J Neurochem. 2006;96:1016–27.

    Article  PubMed  CAS  Google Scholar 

  123. Barker JM, Galea LA. Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats. Neuroscience. 2008;152:888–902.

    Article  PubMed  CAS  Google Scholar 

  124. Forger NG. Control of cell number in the sexually dimorphic brain and spinal cord. J Neuroendocrinol. 2009;21:393–9.

    Article  PubMed  CAS  Google Scholar 

  125. Gough M, Shafafy R, Shortland AP. Does sex influence outcome in ambulant children with bilateral spastic cerebral palsy? Dev Med Child Neurol. 2008;50:702–5.

    Article  PubMed  CAS  Google Scholar 

  126. Johnston MV, Hagberg H. Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol. 2007;49:74–8.

    Article  PubMed  Google Scholar 

  127. Lauterbach MD, Raz S, Sander CJ. Neonatal hypoxic risk in preterm birth infants: The influence of sex and severity of respiratory distress on cognitive recovery. Neuropsychology. 2001;15:411–20.

    Article  PubMed  CAS  Google Scholar 

  128. Christensen J, Kjeldsen MJ, Andersen H, Friis ML, Sidenius P. Gender differences in epilepsy. Epilepsia. 2005;46:956–60.

    Article  PubMed  Google Scholar 

  129. Golomb MR, Fullerton HJ, Nowak-Gottl U, Deveber G. Male predominance in childhood ischemic stroke: findings from the international pediatric stroke study. Stroke. 2009;40:52–7.

    Google Scholar 

  130. Perelman RH, Palta M, Kirby R, Farrell PM. Discordance between male and female deaths due to the respiratory distress syndrome. Pediatrics. 78: 238–44.

  131. Shalev U, Feldon J, Weiner I. Gender- and age-dependent differences in latent inhibition following pre-weaning non-handling: Implications for a neurodevelopmental animal model of schizophrenia. Int J Dev Neurosci. 1998;16:279–88.

    Article  PubMed  CAS  Google Scholar 

  132. Vagnerova K, Koerner IP, Hurn PD. Gender and the injured brain. Anesth Analg. 2008;107:201–14.

    Article  PubMed  Google Scholar 

  133. Kaczmarek L, Kossut M, Skangiel-Kramska J. Glutamate receptors in cortical plasticity: Molecular and cellular biology. Physiol Rev. 1997;77:217–55.

    PubMed  CAS  Google Scholar 

  134. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated ‘menage a trois’. Trends Neurosci. 1997;20:523–9.

    Article  PubMed  CAS  Google Scholar 

  135. Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol. 1998;54:369–415.

    Article  PubMed  CAS  Google Scholar 

  136. Arai Y, Mizuguchi M, Takashima S. Developmental changes of glutamate receptors in the rat cerebral cortex and hippocampus. Anat Embryol. 1997;195:65–70.

    Article  PubMed  CAS  Google Scholar 

  137. Franklin SO, Elliott K, Zhu YS, Wahlestedt C, Inturrisi CE. Quantitation of NMDA receptor (NMDAR1) mRNA levels in the adult and developing rat CNS. Mol Brain Res. 1993;19:93–100.

    Article  PubMed  CAS  Google Scholar 

  138. Riva MA, Tascedda F, Molteni R, Racagni G. Regulation of NMDA receptor subunit mRNA expression in the rat brain during postnatal development. Mol Brain Res. 1994;25:209–16.

    Article  PubMed  CAS  Google Scholar 

  139. Morin AM, Hattori H, Wasterlain CG, Thomson D. [3H]MK-801 binding sites in neonate rat brain. Brain Res. 1989;487:376–9.

    Article  PubMed  CAS  Google Scholar 

  140. Khalilov I, Dzhala V, Medina I, Leinekugel X, Melyan Z, Lamsa K, Khazipov R, Ben-Ari Y. Maturation of kainate-induced epileptiform activities in interconnected intact neonatal limbic structures in vitro. Eur J Neurosci. 1999;11:3468–80.

    Article  PubMed  CAS  Google Scholar 

  141. Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. GABA: A pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215–84.

    Article  PubMed  CAS  Google Scholar 

  142. Kortekaas P, Wadman WJ. Development of HVA and LVA calcium currents in pyramidal CA1 neurons in the hippocampus of the rat. Dev Brain Res. 1997;101:139–47.

    Article  CAS  Google Scholar 

  143. Jones OT, Bernstein GM, Jones EJ, Jugloff DG, Law M, Wong W, Mills LR. N-Type calcium channels in the developing rat hippocampus: Subunit, complex, and regional expression. J Neurosci. 1997;17:6152–64.

    PubMed  CAS  Google Scholar 

  144. Chameau P, Lucas P, Melliti K, Bournaud R, Shimahara T. Development of multiple calcium channel types in cultured mouse hippocampal neurons. Neuroscience. 1999;90:383–8.

    Article  PubMed  CAS  Google Scholar 

  145. Boukhaddaoui H, Sieso V, Scamps F, Vigues S, Roig A, Valmier J. Q- and L-type calcium channels control the development of calbindin phenotype in hippocampal pyramidal neurons in vitro. Eur J Neurosci. 2000;12:2068–78.

    Article  PubMed  CAS  Google Scholar 

  146. Tanaka O, Sakagami H, Kondo H. Localization of mRNAs of voltage-dependent Ca(2+)-channels: Four subtypes of alpha 1- and beta-subunits in developing and mature rat brain. Mol Brain Res. 1995;30:1–16.

    Article  PubMed  CAS  Google Scholar 

  147. Pravettoni E, Bacci A, Coco S, Forbicini P, Matteoli M, Verderio C. Different localizations and functions of L-type and N-type calcium channels during development of hippocampal neurons. Dev Biol. 2000;227:581–94.

    Article  PubMed  CAS  Google Scholar 

  148. Nuñez JL, McCarthy MM. Evidence for an extended duration of GABA-mediated excitation in the developing male versus female hippocampus. 2007;67:1879–90.

  149. Leinekugel X, Khalilov I, McLean H, Caillard O, Gaiarsa JL, Ben-Ari Y, Khazipov R. GABA is the principal fast-acting excitatory transmitter in the neonatal brain. Adv Neurol. 1999;79:189–201.

    PubMed  CAS  Google Scholar 

  150. Leinekugel X, Tseeb V, Ben-Ari Y, Bregestovski P. Synaptic GABAA activation induces Ca2+ rise in pyramidal cells and interneurons from rat neonatal hippocampal slices. J Physiol. 1995;487:319–29.

    PubMed  CAS  Google Scholar 

  151. Ben-Ari Y. Developing networks play a similar melody. Trends Neurosci. 2001;24:353–60.

    Article  PubMed  CAS  Google Scholar 

  152. Leinekugel X, Medina I, Khalilov I, Ben-Ari Y, Khazipov R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABA(A) and NMDA receptors in the neonatal hippocampus. Neuron. 1997;18:243–55.

    Article  PubMed  CAS  Google Scholar 

  153. Soriano E, Cobas A, Fairen A. Asynchronism in the neurogenesis of GABAergic and non-GABAergic neurons in the mouse hippocampus. Brain Res. 1986;395:88–92.

    Article  PubMed  CAS  Google Scholar 

  154. Rothe T, Middleton-Price H, Bigl V. The ontogeny of GABA receptors and glutamic acid decarboxylase in regions of the rat brain. Effect of prenatal exposure to diazepam. Neuropharmacology. 1988;27:661–7.

    Article  PubMed  CAS  Google Scholar 

  155. Owens DF, Boyce LH, Davis MB, Kriegstein AR. Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J Neurosci. 1996;16:6414–23.

    PubMed  CAS  Google Scholar 

  156. Obrietan K, van den Pol AN. GABA neurotransmission in the hypothalamus: Developmental reversal from Ca2+ elevating to depressing. J Neurosci. 1995;15:5065–77.

    PubMed  CAS  Google Scholar 

  157. Owens DF, Liu X, Kriegstein AR. Changing properties of GABA(A) receptor-mediated signaling during early neocortical development. J Neurophysiol. 1999;82:570–83.

    PubMed  CAS  Google Scholar 

  158. Cherubini E, Gaiarsa JL, Ben-Ari Y. GABA: An excitatory transmitter in early postnatal life. Trends Neurosci. 1991;14:515–9.

    Article  PubMed  CAS  Google Scholar 

  159. Ganguly K, Schinder AF, Wong ST, Poo M. GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell. 2001;105:521–32.

    Article  PubMed  CAS  Google Scholar 

  160. Rego AC, Lambert JJ, Nicholls DG. Developmental profile of excitatory GABA(A) responses in cultured rat cerebellar granule cells. Neuroreport. 2001;12:477–82.

    Article  PubMed  CAS  Google Scholar 

  161. Plotkin MD, Snyder EY, Hebert SC, Delpire E. Expression of the Na-K-2Cl cotransporter is developmentally regulated in postnatal rat brains: A possible mechanism underlying GABA’s excitatory role in immature brain. J Neurobiol. 1997;33:781–95.

    Article  PubMed  CAS  Google Scholar 

  162. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397:251–5.

    Article  PubMed  CAS  Google Scholar 

  163. Sung KW, Kirby M, McDonald MP, Lovinger DM, Delpire E. Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. J Neurosci. 2000;20:7531–8.

    PubMed  CAS  Google Scholar 

  164. Kanaka C, Ohno K, Okabe A, Kuriyama K, Itoh T, Fukuda A, Sato K. The differential expression patterns of messenger RNAs encoding K-Cl cotransporters (KCC1,2) and Na-K-2Cl cotransporter (NKCC1) in the rat nervous system. Neuroscience. 2001;104:933–46.

    Article  PubMed  CAS  Google Scholar 

  165. Hubner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001;30:515–24.

    Article  PubMed  CAS  Google Scholar 

  166. Marty S, Wehrle R, Alvarez-Leefmans FJ, Gasnier B, Sotelo C. Postnatal maturation of Na+, K+, 2Cl- cotransporter expression and inhibitory synaptogenesis in the rat hippocampus: An immunocytochemical analysis. Eur J Neurosci. 2002;15:233–45.

    Article  PubMed  Google Scholar 

  167. Barna B, Kuhnt U, Siklos L. Chloride distribution in the CA1 region of newborn and adult hippocampus by light microscopic histochemistry. Histochem Cell Biol. 2001;115:105–16.

    PubMed  CAS  Google Scholar 

  168. Andine P, Orwar O, Jacobson I, Sandberg M, Hagberg H. Changes in extracellular amino acids and spontaneous neuronal activity during ischemia and extended reflow in the CA1 of the rat hippocampus. J Neurochem. 1991;57:222–9.

    Article  PubMed  CAS  Google Scholar 

  169. Globus MY, Busto R, Martinez E, Valdes I, Dietrich WD, Ginsberg MD. Comparative effect of transient global ischemia on extracellular levels of glutamate, glycine, and gamma-aminobutyric acid in vulnerable and nonvulnerable brain regions in the rat. J Neurochem. 1991;57:470–8.

    Article  PubMed  CAS  Google Scholar 

  170. Andine P, Sandberg M, Bagenholm R, Lehmann A, Hagberg H. Intra- and extracellular changes of amino acids in the cerebral cortex of the neonatal rat during hypoxic-ischemia. Dev Brain Res. 1991;64:115–20.

    Article  CAS  Google Scholar 

  171. Hagberg H, Lehmann A, Sandberg M, Nystrom B, Jacobson I, Hamberger A. Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. J Cereb Blood Flow Metab. 1985;5:413–9.

    Article  PubMed  CAS  Google Scholar 

  172. Johansen FF, Christensen T, Jensen MS, Valente E, Jensen CV, Nathan T, Lambert JD, Diemer NH. Inhibition in postischemic rat hippocampus: GABA receptors, GABA release, and inhibitory postsynaptic potentials. Exp Brain Res. 1991;84:529–37.

    Article  PubMed  CAS  Google Scholar 

  173. Campochiaro P, Coyle JT. Ontogenetic development of kainate neurotoxicity: Correlates with glutamatergic innervation. Proc Natl Acad Sci USA. 1978;75:2025–9.

    Article  PubMed  CAS  Google Scholar 

  174. Jensen FE. The role of glutamate receptor maturation in perinatal seizures and brain injury. Int J Dev Neurosci. 2002;20:339–47.

    Article  PubMed  CAS  Google Scholar 

  175. Marks JD, Friedman JE, Haddad GG. Vulnerability of CA1 neurons to glutamate is developmentally regulated. Dev Brain Res. 1996;97:194–206.

    Article  CAS  Google Scholar 

  176. Nuñez JL, Alt JJ, McCarthy MM. A novel model for prenatal brain damage. II. Long-term deficits in hippocampal cell number and hippocampal-dependent behavior following neonatal GABAA receptor activation. Exp Neurol. 2003;181:270–80.

    Article  PubMed  CAS  Google Scholar 

  177. Brunet C, Luyckx M, Lhermitte M. Acid metabolite of progabide pharmacokinetics following single administration in the rabbit with special references to HPLC and (3H) muscimol radioreceptor assay. Eur J Drug Metab Pharmacokinet. 1989;14:257–62.

    Article  PubMed  CAS  Google Scholar 

  178. Nuñez JL, McCarthy MM. Cell death in the rat hippocampus in a model of prenatal brain injury: Time course and expression of death-related proteins. Neuroscience. 2004;129:393–402.

    Article  PubMed  CAS  Google Scholar 

  179. Clancy B, Finlay BL, Darlington RB, Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007;28:931–7.

    Article  PubMed  Google Scholar 

  180. Wise PM, Dubal DB, Wilson ME, Rau SW, Böttner M, Rosewell KL. Estradiol is a protective factor in the adult and aging brain: Understanding of mechanisms derived from in vivo and in vitro studies. Brain Res Brain Res Rev. 2001;37:313–9.

    Article  PubMed  CAS  Google Scholar 

  181. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20:631–52.

    Article  PubMed  CAS  Google Scholar 

  182. Nuñez JL, McCarthy MM. Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury. Endocrinology. 2003;144:2350–9.

    Article  PubMed  CAS  Google Scholar 

  183. Mong JA, Glaser E, McCarthy MM. Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner. J Neurosci. 1999;19:1464–72.

    PubMed  CAS  Google Scholar 

  184. Nuñez JL, Bambrick LL, Krueger BK, McCarthy MM. Prolongation and enhancement of gamma-aminobutyric acid receptor mediated excitation by chronic treatment with estradiol in developing rat hippocampal neurons. Eur J Neurosci. 2005;221:3251–61.

    Article  Google Scholar 

  185. Nuñez JL, McCarthy MM. Evidence for an extended duration of GABA-mediated excitation in the developing male versus female hippocampus. Dev Neurobiol. 2007;67:1879–90.

    Article  PubMed  CAS  Google Scholar 

  186. Liu M, Oyarzabal EA, Yang R, Murphy SJ, Hurn PD. A novel method for assessing sex-specific and genotype-specific responses to injury in astrocyte culture. J Neurosci Methods. 2008;171:214–7.

    Article  PubMed  CAS  Google Scholar 

  187. Barron S, Mulholland PJ, Littleton JM, Prendergast MA. Age and gender differences in response to neonatal ethanol withdrawal and polyamine challenge in organotypic hippocampal cultures. Alcohol Clin Exp Res. 2008;32:929–36.

    Article  PubMed  CAS  Google Scholar 

  188. Johnsen D, Murphy SJ. Isoflurane preconditioning protects neurons from male and female mice against oxygen and glucose deprivation and is modulated by estradiol only in neurons from female mice. Neuroscience. 2011;199:268–374.

    Article  CAS  Google Scholar 

  189. Döhler KD, Wuttke W. Changes with age in levels of serum gonadotropins, prolactin and gonadal steroids in prepubertal male and female rats. Endocrinology. 1975;97:898–907.

    Article  PubMed  Google Scholar 

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Nuñez, J. Sex and steroid hormones in early brain injury. Rev Endocr Metab Disord 13, 173–186 (2012). https://doi.org/10.1007/s11154-012-9219-3

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